The present invention is directed to a polymorph of the citric acid salt of 4-(3,4-dichlorophenyl)-2-[2-(4-methylpiperazin-1-yl)-benzylidene]-thiomorpholin-3-one: 
and pharmaceutical compositions thereof.
The compound, 4-(3,4-dichlorophenyl)-2-[2-(4-methylpiperazin-1-yl )-benzylidene]-thiomorpholin-3-one, is an antagonist of the serotonin-1D (5-HT1D) receptor and is useful in the treatment of a number of disorders, diseases and conditions of the central nervous system. This compound is particularly useful in the treatment of hypertension, all forms of depression, depression in cancer patients, depression in Parkinson""s patients, postmyocardial infarction depression, subsyndromal symptomatic depression, depression in infertile women, pediatric depression, major depressive disorder, single episode depression, recurrent depression, child abuse induced depression, post partum depression, dysthymia; mild, moderate, or severe depressions with or without atypical features, melancholic features, psychotic features, catatonic features; seasonal affective disorder, geriatric depression, chronic depression; adjustment disorder with depressed mood or with anxiety and depressed mood; mixed anxiety and depression; substance induced mood disorder; and mood disorder secondary to a general medical condition, bipolar disorder, bipolar disorder-depressed phase, generalized anxiety disorder, phobias, agoraphobia, social anxiety, social phobia, simple phobias, separation anxiety disorder, posttraumatic stress syndrome, avoidant personality disorder, premature ejaculation, eating disorders, binge eating disorder, anorexia nervosa, bulimia nervosa, obesity; chemical dependencies and addictions to alcohol, cocaine, heroin, phenobarbital, nicotine, marijuana and benzodiazepines; cluster headache, migraine, pain, Alzheimer""s disease, obsessive-compulsive disorder, panic disorder, panic disorder with agoraphobia, memory disorders, dementia, amnestic disorders, and age-related cognitive decline (ARCD), Parkinson""s diseases, dementia in Parkinson""s disease, neuroleptic-induced parkinsonism and tardive dyskinesias, endocrine disorders, hyperprolactinaemia, vasospasm, vasospasm in the cerebral vasculature, cerebellar ataxia; gastrointestinal tract disorders involving changes in motility and secretion; negative symptoms of schizophrenia, premenstrual syndrome, fibromyalgia syndrome, stress incontinence, Tourette""s syndrome, trichotillomania, kleptomania, male impotence, cancer, small cell lung carcinoma, chronic paroxysmal hemicrania, headache associated with vascular disorders, autism, pervasive developmental disorder NOS, Asperger""s disorder, selective mutism, chronic motor or vocal tic disorder, somatization disorder, insomnia, intermittent explosive disorder, pyromania, pathological gambling, impulse-control disorder, premenstrual dysphoric disorder and attention-deficit/hyperactivity disorder (ADHD) in a mammal, particularly a human. The citrate salt of this invention may also be used in a pharmaceutical composition in combination with a serotonin reuptake inhibiting antidepressant (SRI), in order to treat a number of these conditions.
Compounds that are antagonists of the serotonin-1D receptor, including 4-(3,4-dichlorophenyl)-2-[2-(4-methylpiperazin-1-yl)-benzylidene]-thiomorpholin-3-one, specifically including its hydrochloride salt, are referred to in WO 98/14433, published Apr. 9, 1998 (corresponding to U.S. Ser. No. 09/254,999, filed Oct. 8, 1999, now U.S. Pat. No. 6,380,186, Ser. No. 09/733346, filed Dec. 8, 2000, now U.S. Pat. No. 6,423,708 and PCT/IB01/02139, filed Nov. 12, 2001). The foregoing applications, owned in common with the present application and incorporated herein by reference in their entirety, generically recite pharmaceutically acceptable acid addition salts for the compounds referred to therein.
The citrate salt of the present invention exhibits properties, including those of solid-state stability and compatibility with certain drug product formulation excipients, that render it superior to previously known salts of 4-(3,4-dichlorophenyl)-2-[2-(4-methylpiperazin-1-yl)-benzylidene]-thiomorpholin-3-one.